Reproductive and Developmental Toxicity Study of Hexachloroacetone Administered to Sprague Dawley Rats in the Drinking Water

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

The potential toxicity of hexachloroacetone was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to hexachloroacetone exposure.

The dose range-finding study was conducted at concentrations of 0, 39, 156, 625, and 2500 ppm of HCA in the drinking water for two weeks. However, the 2500 ppm animals were euthanized on SD 9 as a result of extreme decreases in body weight, and feed and water consumption. Based on decreased body weight and water consumption in the 625 ppm males and females, the dose levels of 0, 25, 100, and 400 ppm were selected for the main study, which utilized one group of male rats (10 per dose level) and two groups of female rats designated as Group A (peri-conception exposure, 10 per dose level) and Group B (gestational exposure, 13 per dose level). Control animals received deionized water, the vehicle.

During the treatment period, all animals survived to the scheduled necropsy and there were no clinical signs of general toxicity noted at any dose level. At most intervals during the study, water consumption was decreased in all of the 400 ppm animals by 21-51%. The 25 ppm males water consumption was decreased on SD 8 and 33 by 14-25%, while the 100 ppm males consumption was decreased on SD 21-33 by 15-24%. The overall calculated consumption of HCA for Groups 2-4 was 2.8, 10.8, and 32.2 mg/kg/day, respectively. Male and female mean absolute body weights, feed consumption, clinical observations, and gross findings were comparable across dose groups. Female and male reproductive findings were also comparable with the exception of a 16% decrease in the number of corpora lutea in the 400 ppm Group A females, a 32% increase in the number of live male pups in the 400 ppm Group B females, and an increase of 25%, 27%, and 29% in the circular sperm, circular over all sperm, and circular over motile sperm, respectively, in the 400 ppm male computer-assisted sperm analysis. The 16% decrease in 400 ppm number of corpora lutea was accompanied by a decrease (pgreater than 0.05) in pre-implantation loss (33%). These findings may suggest that hexachloroacetone may inhibit ovulation, but due to the limited number of females, this result requires replication before being relied on, and furthermore, there is effectively no change in the Group A or B female litter size. Although there was an increase of 32% in the Group B live male pups, the proportion of males/total pups (.54) is not statistically significant and is well within historical control data (.42 - .61) compiled by MARTA (MARTA, 1996). Computer-assisted sperm analysis in the 400 ppm males revealed an increase of 25-29% in circular sperm, % circular over all sperm, and % circular over motile sperm, but with the lack of other male reproductive findings and lack of literature on these parameters, the real meaning of this effect is undetermined. Male organ weights, organ-to-body weight ratios, and clinical chemistry and hematology endpoints were also unaffected by HCA treatment.

Results of this study indicate that HCA treatment reduced water consumption in the 400 ppm dose levels in males and females without affecting reproductive function. A maximum tolerated dose in both males and females was achieved at 400 ppm HCA based on a greater than 20% reduction in water consumption. From these data, HCA may be taste-aversive at 400 ppm in male and female rats and is not a reproductive toxicant in males; however, HCA is a reproductive toxicant in females at a dose level of 400 ppm when rats are exposed to HCA for less than or equal to 35 days.